Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines. Some cytotoxic analogues also significantly suppressed the growth of mammary and prostate cancers in vivo in animal models.
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PMID:Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups. 131 May 42

In vitro 1H NMR spectra were acquired for perchloric acid extracts of tissue samples of human prostate. Seven patients were diagnosed with prostate cancer, 13 with benign prostatic hypertrophy, and 3 with both conditions. Statistically significant differences between the cancer and benign groups were seen for the metabolite peak area ratios of citrate, creatine, and phosphorylcholine to alanine, and citrate to glutamate. There was no correlation of Gleason grade with any of the ratios measured for the cancer samples. Spectra from different sections of large tumors often yielded substantially different area ratios, confirming the heterogeneous nature of these prostate tumors.
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PMID:Differentiation of human prostate cancer from benign hypertrophy by in vitro 1H NMR. 137 2

The gene for the androgen receptor (AR) in the androgen-sensitive human prostate cancer cell line LNCaP has a single-base mutation that produces a threonine to alanine change in the androgen-binding domain. Androgen-insensitive prostatic cancer (PC-3) cells were cotransfected with an expression vector encoding normal, LNCaP, or chimeric normal/LNCaP AR and a vector carrying a chloramphenicol acetyltransferase (CAT) reporter gene linked to the mouse mammary tumor virus promoter. CAT activity was specifically induced by androgens in PC-3 cells expressing normal AR. In PC-3 cells expressing LNCaP AR, however, CAT activity was also induced by progestins and the antiandrogen hydroxyflutamide, which had little activity in cells expressing normal AR. Steroid-binding competition assays using in vitro synthesized ARs showed that LNCaP AR had a higher affinity than normal AR for progestins, 17 beta-estradiol, and hydroxyflutamide. The antiprogestin and antiglucocorticoid RU 38486 induced CAT activity in PC-3 cells expressing normal AR but not LNCaP AR. These studies indicate that AR mutations may be very important in determining the appropriate method of treatment with steroid hormones or their antagonists.
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PMID:Expression and function of normal and LNCaP androgen receptors in androgen-insensitive human prostatic cancer cells. Altered hormone and antihormone specificity in gene transactivation. 166 32

Sexual-steroid-hormone-linked anticancer agents are a new group of cytotoxic drugs designed for a site-directed chemotherapy of tumors containing sexual steroid hormone receptors. The hormone (e.g. estradiol or testosterone) should act as a carrier that leads to a preferential receptor-mediated drug accumulation in hormone-receptor-positive tumors (such as mammary carcinomas and prostatic cancer). In several preclinical therapeutic studies of sexual-hormone-receptor-positive breast cancer, for instance, conjugates of 2-chloroethyl-carbamoyl-L-alanine linked to estradiol or dihydrotestosterone showed, in comparison to the unlinked single agent, a significantly higher antineoplastic activity and a clearly lower systemic toxicity. But there is still only limited knowledge about the pharmacokinetic properties and the mode of action of these new drugs. For this reason in the present article a more comprehensive pharmacokinetic model and the pattern of distribution of new sexual-steroid-hormone-linked anticancer agents have been described.
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PMID:The pharmacokinetic model and distribution pattern of new sexual-steroid-hormone-linked anticancer agents. 222 35

In our previous report, monoclonal antibody PR92 has defined prostate- and breast tumor-associated PR92 antigen. The molecular nature of PR92 antigen, especially the epitope involved in specific interaction with PR92 monoclonal antibody, is described. PR92 antigen was purified from the cell extract or tissue culture medium of prostate cancer cell line DU145 by means of monoclonal antibody-coupled Sepharose 4B affinity chromatography, followed by a Sephacryl S-500 chromatography. Physical and chemical characterization, coupled with high-performance liquid chromatography, determined that PR92 antigen is a glycoprotein with a molecular weight of about 470,000, comprising repeating subunits of about 44,000. Sialic acid was found to form a critical part, while D-galactose and N-acetylgalactosamine were also involved, in the epitope structure. PR92 antigen is rich in serine, threonine, proline, glycine, and alanine and poor in aromatic amino acid residues. The carbohydrate moieties may be predominantly O-linked to polypeptide chains which contribute directly or indirectly to maintain the integrity of the epitope. Elucidation of the molecular nature of PR92 antigen may help understand the mechanism of shedding into the body fluids during tumor progression.
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PMID:Molecular characterization of the epitope in prostate and breast tumor-associated PR92 antigen. 246 8

Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. For instance, SB-40, a PtCl2-containing metallopeptide in which platinum is coordinated to an N epsilon-(DL-2,3-diaminopropionyl)-D-lysine residue [D-Lys(DL-A2pr] at position 6, showed 50 times higher LH-releasing potency than the native hormone. SB-95, [Ac-D-Nal(2)1,D-Phe(pCl)2, D-Pal(3)2, Arg5,D-Lys[DL-A2pr(Sal2Cu)]6,D-Ala10]LH-RH, where Nal(2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and copper(II) is coordinated to the salicylideneimino moieties resulting from condensation of salicylaldehyde with D-Lys(DL-A2pr)6, caused 100% inhibition of ovulation at a dose of 3 micrograms in rats. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer cell lines in vitro (this will be the subject of a separate paper on cytotoxicity evaluation). Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.
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PMID:Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone. 254 6

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.
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PMID:Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6. 254 7

The determination of gamma-seminoprotein (gamma-Sm) (also called prostate-specific antigen [PSA], prostate antigen [PA], or p30) in human serum has been recently demonstrated to be more sensitive and specific for diagnosing prostate cancer and monitoring the condition of patients with prostate cancer than the prostatic acid phosphatase (PAP) test. Because the gamma-Sm (PSA) test seems likely to replace the PAP test in the area of urology and study of prostate-specific antigens is expanding, we have reviewed physicochemical properties and clinical significance of two prostate-specific antigens, gamma-Sm (PSA) and beta-microseminoprotein (beta-MSP). Both proteins have been proved to originate in the prostate gland and have not been detected in any other human tissues by an immunohistologic study. The usefulness of gamma-Sm and beta-MSP in determining the origin of metastatic tumors has also been shown. gamma-Sm is a glycoprotein with a molecular weight of 26,079 for the peptide portion, of which the amino acid sequence is identical to so-called PSA and homologous with serine proteases (the kallikrein family). Its chymotrypsin-like activity with a unique substrate specificity has also been demonstrated. The molecular weight of beta-MSP is 10,652 from the amino acid sequence, in which the protein has been shown to contain no alanine residue.
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PMID:Two prostate-specific antigens, gamma-seminoprotein and beta-microseminoprotein. 265 6

The mechanism of antiandrogenic activity of vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione), a dicarboximide fungicide under investigation for its potential adverse effects on human male reproduction, was investigated using recombinant human androgen receptor (AR). The two primary metabolites of vinclozolin in plants and mammals are M1 (2-[[3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid) and M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide). Both metabolites, in a dose-dependent manner, target AR to the nucleus and inhibit androgen-induced transactivation mediated by the mouse mammary tumor virus promoter. M2 is a 50-fold more potent inhibitor than M1 and only 2-fold less than hydroxyflutamide. In the presence of dihydrotestosterone (50 nM), M2 (0.2-10 microM) inhibits androgen-induced AR binding to androgen response element DNA. In the absence of dihydrotestosterone, concentrations of 10 microM M2 or hydroxyflutamide promote AR binding to androgen response element DNA and activation of transcription. Agonist activities of M2 and hydroxyflutamide occur at 10-fold lower concentrations with the mutant AR (Thr877 to Ala) endogenous to LNCaP human prostate cancer cells. The results indicate that androgen antagonists can act as agonists, depending on ligand binding affinity, concentration, and the presence of competing natural ligands.
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PMID:Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide. 765 17

In vitro 1H and 31P magnetic resonance spectra were acquired from perchloric acid extracts of human prostate tissue obtained by transurethral resection. This included tissue of patients with benign prostatic hyperplasia and prostatic adenocarcinoma; one tissue sample was obtained from a patient without any sign of BPH or malignancy. Major resonances in the magnetic resonance spectra were assigned to prostate compounds and were quantified. The citrate/lactate, citrate/total choline, phosphocholine/total creatinine, choline/total creatine, alanine/total creatine, phosphoethanolamine/total phosphate, phosphocholine/total phosphate and glycerophosphoethanolamine/total phosphate ratios were statistically different for the prostate cancer samples as compared with the BPH specimens. These observations may contribute to the understanding of in vivo magnetic resonance spectra of the prostate and indicate that magnetic resonance spectroscopy can aid in the diagnosis of prostate malignancy.
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PMID:Characterization of human prostate cancer, benign prostatic hyperplasia and normal prostate by in vitro 1H and 31P magnetic resonance spectroscopy. 769 85


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